Method of treating diabetes and related disease states

ABSTRACT

The instant invention is concerned with acetylphenols which are useful as antiobesity and antidiabetic compounds. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering or modulating triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility or for treating atherosclerosis are also disclosed.

This application is a continuation-in part and claims priority to U.Sprovisional application: application Ser. No. 60/011025 filed Feb. 2,1996 which is herein incorporated by reference in its entirety.

This application is a continuation-in part and claims priority to U.Sprovisional application: application Ser. No. 60/011025 filed Feb. 2,1996 which is herein incorporated by reference in its entirety.

This application is related to the following U.S. non-provisionalapplications: Ser. No. 08/797,650 filed Jan. 31, 1997 which is hereinincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia. Uncontrolled hyperglycemia is associated with increasedand premature mortality due to an increased risk for microvascular andmacrovascular diseases, including nephropathy, neuropathy, retinopathy,hypertension, stroke, and heart disease. Therefore, control of glucosehomeostasis is a critically important approach for the treatment ofdiabetes.

Type I diabetes (IDDM) is the result of an absolute deficiency ofinsulin, the hormone which regulates glucose utilization. Type II,noninsulin dependent diabetes mellitus (NIDDM) is due to a profoundresistance to insulin stimulating or regulatory effect on glucose andlipid metabolism in the main insulin-sensitive tissues, muscle, liverand adipose tissue. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in liver.

The several treatments for NIDDM, which has not changed substantially inmany years, are all with limitations. While physical exercise andreductions in dietary intake of calories will dramatically improve thediabetic condition, compliance with this treatment is very poor becauseof well-entrenched sedentary lifestyles and excess food consumption,especially high fat-containing food. Increasing the plasma level ofinsulin by administration of sulfonylureas (e.g. tolbutamide, glipizide)which stimulate the pancreatic β-cells to secrete more insulin or byinjection of insulin after the response to sulfonylureas fails, willresult in high enough insulin concentrations to stimulate the veryinsulin-resistant tissues. However, dangerously low levels of plasmaglucose can result from these last two treatments and increasing insulinresistance due to the even higher plasma insulin levels couldtheoretically occur. The biguanides increase insulin sensitivityresulting in some correction of hyperglycemia. However, the twobiguanides, phenformin and metformin, can induce lactic acidosis andnausea/diarrhea, respectively.

Thiazolidinediones (glitazones) are a recently disclosed class ofcompounds that are suggested to ameliorate many symptoms of NIDDM. Theseagents increase insulin sensitivity in muscle, liver and adipose tissuein several animal models of NIDDM resulting in complete correction ofthe elevated plasma levels of glucose, triglycerides and nonesterifiedfree fatty acids without any occurrence of hypoglycemia. However,serious undesirable effects have occurred in animal and/or human studiesincluding cardiac hypertrophy, hemadilution and liver toxicity resultingin few glitazones progressing to advanced human trials.

Hyperlipidemia is a condition which is characterized by an abnormalincrease in serum lipids, such as cholesterol, triglycerides andphospholipids. These lipids do not circulate freely in solution inplasma, but are bound to proteins and transported as macromolecularcomplexes called lipoproteins. See the Merck Manual, 16th Ed. 1992 (seefor example pp. 1039-1040) and "Structure and Metabolism of PlasmaLipoproteins" in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp.1129-1138. One form of hyperlipidemia is hypercholesterolemia,characterized by the existence of elevated LDL cholesterol levels. Theinitial treatment for hypercholesterolemia is often to modify the dietto one low in fat and cholesterol, coupled with appropriate physicalexercise, followed by drug therapy when LDL-lowering goals are not metby diet and exercise alone. LDL is commonly known as the "bad"cholesterol, while HDL is the "good" cholesterol. Although it isdesirable to lower elevated levels of LDL cholesterol, it is alsodesirable to increase levels of HDL cholesterol. Generally, it has beenfound that increased levels of HDL are associated with lower risk forcoronary heart disease (CHD). See, for example, Gordon, et al., Am. J.Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med., 325,373-381 (1991); and Kannel, et al., Ann. Internal Med., 90, 85-91(1979). An example of an HDL raising agent is nicotinic acid, but thequantities needed to achieve HDL raising are associated with undesirableeffects, such as flushing.

It is suggested that thiazolidinedione compounds exert their effects bybinding to the peroxisome proliferator activated receptor (PPAR) familyof receptors, controlling certain transcription elements having to dowith the biological entities listed above. See Hulin et al., CurrentPharm. Design (1996) 2, 85-102. Three sub-types of PPARs have beendiscovered and described; they are PPARα, PPARγand PPARδ. PPARα isactivated by a number of medium and long-chain fatty acids, and it isinvolved in stimulating β-oxidation of fatty acids. PPARAα is alsoinvolved with the activity of fibrates in rodents and humans. Fibricacid derivatives such as clofibrate, fenofibrate, bezafibrate,ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil,produce a substantial reduction in plasma triglycerides along withmoderate reduction in LDL cholesterol, and they are used particularlyfor the treatment of hypertriglyceridemia.

The PPARγ receptor subtypes are involved in activating the program ofadipocyte differentiation and are not involved in stimulating peroxisomeproliferation in the liver. The DNA sequences for the PPARγ receptorsare described in Elbrecht, et al., BBRC 224;431-437 (1996). Althoughperoxisome proliferators, including the fibrates and fatty acids,activate the transcriptional activity of PPAR's, only prostaglandin J₂derivatives have been identified as natural ligands of the PPARγsubtype, which also binds thiazolidinedione antidiabetic agents withhigh affinity. The glitazones have been shown to bind exclusively to thePPARγ subtype.

The human nuclear receptor gene PPARδ (hPPARδ) has been cloned from ahuman osteosarcoma cell cDNA library and is fully described in A.Schmidt et al., Molecular Endocrinology, 6 :1634-1641 (1992), hereinincorporated by reference. It should be noted that PPARδ is alsoreferred to in the literature as PPARβ and as NUC1, and each of thesenames refers to the same receptor; in Schmidt et al, the receptor isreferred to as NUC1.

SUMMARY OF THE INVENTION

This invention is concerned with the compounds of formula I below andits analogs, pharmaceutically acceptable salts thereof, andbioprecursors thereof, which differ from the thiazolidinediones in thatthey lack the thiazolidinedione moiety and they do not lead to the arrayof toxicity's associated with the thiazolidinediones. The instantcompounds are effective in treating diabetes, atherosclerosis,hyperglycemia, hyperlipidemia and/or obesity because they lower one ormore of the following biological entities in manunals; glucose, insulin,triglycerides, fatty acids, cholesterol and the like. Thus, it is anobject of this invention to describe such compounds. It is a furtherobject to describe the specific preferred stereoisomers of thesubstituted compounds. A still further object is to describe processesfor the preparation of such compounds. Another object is to describemethods and compositions which use the compounds as the activeingredient thereof. Further objects will become apparent from readingthe following description.

DETAILED DESCRIPTION OF THE INVENTION

This invention is a method of using a compound of formula XI or XII:##STR1## or a pharmaceutically acceptable salt or acid addition saltthereof, or a pharmaceutically acceptable ester thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; alkenyl of 2 to 6 carbon atoms which may bestraight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbonatoms which may be straight chain or branched; SH; thioalkyl of 1 to 6carbon atoms which may be straight chain or branched; phenyl; phenylsubstituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl;phenethyl; halogen, amino; N(R₄)₂ wherein R₄ is H or alkyl of 1 to 6carbon atoms which may be straight chain or branched; COOR₄ ; CH₂ OR₄ ;formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R₄ ; OR₄ ; COOR₄ ; N(R₄)₂ ; SR₄ ; CH₂ OR₄ ;CHO; or together R' and R' are O; CH₂ ; or ##STR2##

Y' is sulfur, sulfoxide,sulfone; ##STR3##

R₁₁ is H, alkyl of 1-4 carbon atoms which may be straight chain orbranched; alkanoyl of 1-4 carbon atoms which may be straight chain orbranched; phenylsulfonyl; tosyl; NR₁₂ wherein R₁₂ is H, alkyl of 1-4carbon atoms which may be straight chain or branched; or ##STR4##wherein R₁₃ is alkyl of 1-4 carbon atoms which may be straight chain orbranched, alkoxy of 1-4 carbon atoms which may be straight chain orbranched; N--CN, CH₂, or C═O;

Y is Y' and oxygen;

each R₁ is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R₂ is ##STR5##

each R₆ is independently H or alkyl of 1-4 carbons;

each R₇ is independently H, OH, or alkyl of 1-4 carbons;

each R₈ is independently H, or alkyl of 1-4 carbons, and is absent whena triple bond is present;

R₅ is COOR₄ ; CH₂ OH; CHO; tetrazole; NHSO₂ R₁₄ ; hydroxymethylketone;CN; CON(R₇)₂ ; a monocyclic or bicyclic heterocyclic ring containing anacidic hydroxyl group; or COOR₁₅ where R₁₅ is ##STR6## wherein each s isindependently 0-3;

R₁₆ is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N andS with at least one being N, and with each ring in the heterocyclicradical being formed of 5 or 6 atoms, or

B) the radical W--R₁₇ wherein W is O, S or NH and R₁₇ contains up to 21carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical ofan organic acyclic or monocyclic carboxylic acid containing not morethan 1 heteroatom in the ring;

R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenylsubstituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen,hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms orperfluoroalkyl of 1 to 4 carbon atoms;

r and q are each independently 0-20 provided that the total of r and qdoes not exceed 20;

p is 0 or 1;

R₃ is alkyl of 1 to 6 carbon atoms which may be straight chain orbranched; or alkenyl of 3 to 6 carbon atoms which may be straight chainor branched as illustrated in formulas IV and V;

R₉ is alkyl of 1 to 6 carbon atoms which may be straight chain orbranched; alkoxy of 1 to 6 carbon atoms which may be straight chain orbranched; or (CH₂)_(r) R₅ ; and

R₁₀ is H; alkyl of 1 to 6 carbon atoms which may be straight chain orbranched; ##STR7## or R₄ OCH₂ --.

In one embodiment of the invention the compounds of formula XI and XIIalso include the following:

R₂ is ##STR8## all other definitions remaining the same, except thatwhen one of the R₇ groups is hydroxy, Y' may be oxygen.

As used herein, the terms "each independently" or the equivalentsthereof are employed to described a number of possible position isomersand/or structural variations.

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 15 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred straight or branchedalkyl groups include methyl, ethyl, propyl, isopropyl, butyl andt-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.

Alkyl also includes a straight or branched alkyl group which contains oris interrupted by a cycloalkylene portion. Examples include thefollowing: ##STR9## wherein: x and y=from 0-10; and w and z=from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can beattached at any available point of attachment to the cycloalkyleneportion.

When substituted alkyl is present, this refers to a straight, branchedor cyclic alkyl group as defined above, substituted with 1-3 groups asdefined with respect to each variable.

The term "alkenyl" refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 15 carbon atoms and at least one carbon tocarbon double bond. Preferably one carbon to carbon double bond ispresent, and up to four non-aromatic (non-resonating) carbon-carbondouble bonds may be present. Preferred alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl. As described above with respect toalkyl, the straight, branched or cyclic portion of the alkenyl group maycontain double bonds and may be substituted when a substituted alkenylgroup is provided.

The term "alkynyl" refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 15 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon--carbon triple bonds may bepresent. Preferred alkynyl groups include ethynyl, propynyl and butynyl.As described above with respect to alkyl, the straight, branched orcyclic portion of the alkynyl group may contain triple bonds and may besubstituted when a substituted alkynyl group is provided.

The term alkoxy represents an alkyl group of indicated carbon atomsattached through an oxygen linkage.

The term halo as used herein, represents fluoro, chloro, bromo or iodo.

The compounds of the present invention may be prepared by severaldifferent routes which are well published in the art. See EP 106565 B,incorporated by reference herein in its entirety.

According to one method a compound of formula I is reacted with anoptionally alkyl substituted alkenyl halide of formula II wherein X ishalogen and each R₆ is independently H or alkyl of 1-4 carbon atoms toyield the corresponding 2-hydroxy-4-alkenyloxy-acetophenone of formulaIII. The compound of formula III is then subjected to a Claisenrearrangement to yield a 2,4-dihydroxy-3-alkenyl-acetophenone compoundof formula IV. This rearrangement occurs on heating the compound offormula III either neat or in a high boiling solvent, such as ahalogenated hydrocarbon, e.g., dichlorobenzene, at from about 160° toabout 210° C. The double bond in the compound of formula IV may then bereduced, e.g., by catalytic hydrogenation such as Pd/C, to yield thecorresponding saturated compound of formula V. ##STR10##

The compound of formula V is then reacted with a dihaloalkane of formulaVia or a dihaloalkene of formula VIb wherein X, R and m have the meaninggiven previously, to yield a4-(haloalkyloxy)-3-alkyl-2-hydroxyacetophenone compound of formula VII.The reaction takes place by refluxing a mixture of the compounds offormulas V and VIa or VIb in an inert solvent such as, for example,methylethylketone (MEK), acetone, tetrahydrofuran (THF), triglyme ordichloromethane in the presence of a base. The reflux temperature ispreferably in the range of from about 60° to about 130° C. The base maybe an alkali metal carbonate, for example, Li₂ CO₃, Na₂ CO₃ or K₂ CO₃.

Specific examples of dihaloalkane compounds of formula VIa are1,3-dibromopropane, 2-methyl-1,3-dibromopropane,2,2-dimethyl-1,3-dibromopropane, 3-chloro-2-chloromethyl-1-propene,1,3-dibromobutane, 1,4-dibromobutane, 1,5-dibromopentane,1,6-dibromo-hexane, 1,7-dibromoheptane, 1,8-dibromooctane,1,9-di-bromononane, 1,10-dibromodecane, and 1,12-dibromo-dodecane. Aspecific example of a dihaloalkene compound of formula VIb is1,4-dibromo-2-butene. ##STR11##

A compound of formula II is then react with a compound of formula V toyield a 4-alkenyloxy-3-alkyl-2-hydroxy-aceto-phenone compound of formulaIX which is then epoxidized with an organic peracid such as, forexample, m-chloroperbenzoic acid to give the compound of formula VIII.##STR12##

The reaction of a compound of formula VIII with a compound of formula Xunder the same conditions used to react a compound of formula V with acompound of formula VIa or VIb gives a compound of formula XI or XII.##STR13##

Additional compounds and the method for preparing them included withinthe scope of this invention are disclosed in U.S. Pat. Nos. 5,453,443,4,820,867 and EP 0123541 and EP 0617001, all of which are incorporatedby reference herein in their entirety.

A preferred compound of the instant method is4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2,3-dichlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneaceticacid and its methyl ester;

Sodium Salt of4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneaceticacid, monohydrate and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2-fluorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneaceticacid; and 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-propenylsulfonyl)-2-fluorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-3-fluorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio-3-chlorobenzeneaceticacid and its methyl ester; 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-chlorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-chlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneaceticacid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-thio)benzeneacetic acidand its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-benzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-propylthio)-benzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-benzeneaceticacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoicacid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoicacid and its methyl ester;

4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acidand its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3 -fluorobenzoicacid-S-oxide, methyl ester and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-fluorobenzoic acid and its methyl ester; and

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-cyanamido)-benzeneacetic acid and itsmethyl ester.

Compounds of the general Formula XI or XII may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent, for example methanol or ethylacetate or a mixture thereof. The pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid as a resolving agent.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials of known configuration.

The instant compounds can be isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, malonic and the like. Inaddition, certain compounds containing an acidic function such as acarboxy or tetrazole, can be isolated in the form of their inorganicsalt in which the counterion can be selected from sodium, potassium,lithium, calcium, magnesium and the like, as well as from organic bases.

As previously indicated, the compounds of the present invention havevaluable pharmacological properties. They are useful in treating orpreventing diabetes, treating obesity, lowering triglyceride levels andprevention of vascular restenosis. They are useful in treating otherdisorders where insulin resistance is a component including ovarianhyperandrogenism (polycyctic ovarian syndrome). They are also useful inraising high density lipoprotein levels, preventing, halting or slowingthe progression of atherosclerotic cardiovascular diseases and relatedconditions and disease events.

The present invention also provides a compound of the general Formula Ior a pharmaceutically acceptable salt thereof for use as an activetherapeutic substance.

The present invention further provides a compound of the general FormulaI, or a pharmaceutically acceptable ester thereof; or pharmaceuticallyacceptable salt thereof, for use in the treatment of hyperglycemia(diabetes) in human or non-human animals.

The present invention further provides a compound of the general FormulaI, or a pharmaceutically acceptable ester thereof; or pharmaceuticallyacceptable salt thereof, in combination with known sulfonylureas, otherinsulin secretogogues as well as insulin for use in the treatment ofdiabetes treating obesity, lowering triglyceride levels, prevention ofvascular restenosis, treating other disorders where insulin resistanceis a component including ovarian hyperandrogenism (polycyctic ovariansyndrome), raising high density lipoprotein levels, and preventing,halting or slowing the progression of atherosclerotic cardiovasculardiseases and related conditions and disease events.and hypertension inhuman or non-human animals.

In one aspect, the present invention provides a compound of the generalFormula I for use in the treatment of obesity in human or non-humananimals. Said compound can be effectively used in combination with otherknown or proposed strategies for the treatment of obesity orobesity-related disorders; for example, fenfluramine, dexfenfluramine,phentiramine and β3 adrenergic receptor agonist agents.

The disease diabetes mellitus is characterized by metabolic defects inproduction and utilization of glucose which result in the failure tomaintain appropriate blood sugar levels. The result of these defects iselevated blood glucose or hyperglycemia. Research on the treatment ofdiabetes has centered on attempts to normalize fasting and postprandialblood glucose levels. Treatments have included parenteral administrationof exogenous insulin, oral administration of drugs and dietarytherapies. The instant compounds can be effectively used in combinationwith known therapies for diabetes including insulin, sulfonylureas,biguanides (such as metformin), α-glucosidase inhibitors (such asacarbose) and others.

Two major forms of diabetes mellitus are now recognized. Type Idiabetes, or insulin-dependent diabetes, is the result of an absolutedeficiency of insulin, the hormone which regulates glucose utilization.Type II diabetes, or non-insulin-independent diabetes, often occurs inthe face of normal, or even elevated levels of insulin and appears to bethe result of the inability of tissues to respond appropriately toinsulin. Most of the Type II diabetics are also obese. Accordingly, inanother aspect the present invention provides a method of loweringtriglyceride levels which comprises administering, to an animal in needthereof, a therapeutically effective amount of a compound of the formulaI or pharmaceutically acceptable salt or ester thereof.

In addition the compounds of the present invention lower or modulatetriglyceride levels and/or cholesterol levels and raise HDL plasmalevels and are therefore of use in combating medical conditions whereinsuch lowering (and raising) is thought to be beneficial. Thus they maybe used in the treatment of hypertension, obesity, atheroscleroticdisease events, diabetes and related conditions by administering to ananimal in need thereof, a therapeutically effective amount of a compoundof the formula (I) or pharmaceutically acceptable salt thereof. Thecompositions are formulated and administered in the same general manneras detailed below. They may also contain other active ingredients knownfor use in the treatment of atherosclerotic disease events, diabetes,hypertension, obesity and related conditions, for example fibrates suchas clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterolbiosynthesis such as HMG-CoA reductase inhibitors for examplelovastatin, simvastatin and pravastatin; inhibitors of cholesterolabsorption for example beta-sitosterol and (acyl CoA:cholesterolacyltransferase) inhibitors for example melinamide; anion exchangeresins for example cholestyramine, colestipol or a dialkylaminoalkylderivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acidor a salt thereof; vitamin E; and thyromimetics.

In particular the invention provides methods for preventing or reducingthe risk of developing atherosclerosis, comprising the administration ofa prophylactically effective amount of a compound of formula I alone orin combination with one or more additional pharmaceutically activeagents, to a mammal, particularly human, who is at risk of developingatherosclerosis.

Atherosclerosis encompasses vascular diseases and conditions that arerecognized and understood by physicians practicing in the relevantfields of medicine. Atherosclerotic cardiovascular disease, coronaryheart disease (also known as coronary artery disease or ischemic heartdisease), cerebrovascular disease and peripheral vessel disease are allclinical manifestations of atherosclerosis and are therefore encompassedby the terms "atherosclerosis" and "atherosclerotic disease."

The instant invention further provides methods for preventing orreducing the risk of a first or subsequent (where the potential existsfor recurrence) atherosclerotic disease event, comprising theadministration of a prophylactically effective amount, or moreparticularly an effective amount of a cholesterol biosynthesisinhibitor, of a compound of formula I alone or in combination with oneor more additional pharmaceutically active agents, to a mammal,particularly human, who is at risk for having an atherosclerotic diseaseevent. The term "atherosclerotic disease event" as used herein isintended to encompass coronary heart disease events, cerebrovascularevents, and intermittent claudication. Coronary heart disease events areintended to include CHD death, myocardial infarction (i.e., a heartattack), and coronary revascularization procedures. Cerebrovascularevents are intended to include ischemic or hemorrhagic stroke (alsoknown as cerebrovascular accidents) and transient ischemic attacks.Intermittent claudication is a clinical manifestation of peripheralvessel disease. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease event arethose for whom the potential for recurrence of such an event exists.

Persons to be treated with the instant therapy include those at risk ofdeveloping atherosclerotic disease and of having an atheroscleroticdisease event. Standard atherosclerotic disease risk factors are knownto the average physician practicing in the relevant fields of medicine.Such known risk factors include but are not limited to hypertension,smoking, diabetes, low levels of high density lipoprotein cholesterol,high levels of low density lipoprotein cholesterol, and a family historyof atherosclerotic cardiovascular disease. Published guidelines fordetermining those who are at risk of developing atherosclerotic diseasecan be found in: National Cholesterol Education Program, Second reportof the Expert Panel on Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel II), NationalInstitute of Health, National Heart Lung and Blood Institute, NIHPublication No. 93-3095, September 1993; abbreviated version: ExpertPanel on Detection, Evaluation, and Treatment of High Blood Cholesterolin Adults, Summary of the second report of the national cholesteroleducation program (NCEP) Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (Adult Treatment PanelII), JAMA, 1993, 269, pp. 3015-23. People identified as having one ormore of the above-noted risk factors, as well as people who already haveatherosclerosis, are intended to be included within the group of peopleconsidered to be at risk for having an atherosclerotic disease event.

The active compounds of the present invention may be orally administeredas a pharmaceutical composition, for example, with an inert diluent, orwith an assimilable edible carrier, or they may be enclosed in hard orsoft shell capsules, or they may be compressed into tablets, or they maybe incorporated directly with the food of the diet. For oral therapeuticadministration, which includes sublingual administration, these activecompounds may be incorporated with excipients and used in the form oftablets, pills, capsules, ampules, sachets, elixirs, suspensions,syrups, and the like. Such compositions and preparations should containat least 0.1 percent of active compound. The percentage of activecompound in these compositions may, of course, be varied and mayconveniently be between about 2 percent to about 60 percent of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained. The active compounds can also be administeredintranasally as, for example, liquid drops or spray.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia, or obesity, or when treating, preventing orslowing the progression of atherosclerosis generally satisfactoryresults are obtained when the compounds of the present invention areadministered at a daily dosage of from about 0.1 milligram to about 100milligram per kilogram of animal body weight, preferably given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, preferably fromabout 1 milligrams to about 50 milligrams. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 milligrams toabout 350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

The compositions are formulated and administered in the same generalmanner as detailed below. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of formula I and one or moreadditional active agents, as well as administration of a compound offormula I and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of formula I and an HMG-CoAreductase inhibitor can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, a compound of formual I and one or moreadditional active agents can be administered at essentially the sametime, i.e., concurrently, or at separately staggered times, i.e,sequentially; combination therapy is understood to include all theseregimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of formula I is administered in combination withone or more of the following active agents: an antihyperlipidemic agent;a plasma HDL-raising agent; an antihypercholesterolemic agent such as acholesterol biosynthesis inhibitor, for example an HMG-CoA reductaseinhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidaseinhibitor, or a squalene synthetase inhibitor (also known as squalenesynthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferase(ACAT) inhibitor such as melinamide; probucol; nicotinic acid and thesalts thereof and niacinamide; a cholesterol absorption inhibitor suchas beta-sitosterol; a bile acid sequestrant anion exchange resin such ascholestyramine, colestipol or dialkylaminoalkyl derivatives of across-linked dextran; an LDL (low density lipoprotein) receptor inducer;fibrates such as clofibrate, bezafibrate, fenofibrate, and gemfibrizol;vitamin B₆ (also known as pyridoxine) and the pharmaceuticallyacceptable salts thereof such as the HCl salt; vitamin B ₁₂ (also knownas cyanocobalamin); anti-oxidant vitamins such as vitamin C and E andbeta carotene; a beta-blocker; an angiotensin II antagonist; anangiotensin converting enzyme inhibitor; and a platelet aggregationinhibitor such as fibrinogen receptor antagonists (i.e., glycoproteinIIb/IIIa fibrinogen receptor antagonists) and aspirin. As noted above,the compounds of formula I can be administered in combination with morethan one additional active agent, for example, a combination of acompound of formula I with an HMG-CoA reductase inhibitor (e.g.lovastatin, simvastatin and pravastatin) and aspirin, or a compound offormula I with an HMG-CoA reductase inhibitor and a beta blocker.

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the compounds of formula I may beeffectively used in combination with for example, fenfluramine,dexfenfluramine, phentiramine and β3 adrenergic receptor agonist agents.

Still another example of combination therapy can be seen in treatingdiabetes and related disorders wherein the compounds of formula I can beeffectively used in combination with for example sulfonylureas,biguanides, α-glucosidase inhibitors, other insulin secretogogues,insulin as well as the active agents discussed above for treatingatherosclerosis.

In accordance with this invention, a pharmaceutically effective amountof a compound of formula I can be used for the preparation of amedicament useful for treating diabetes, treating obesity, loweringtryglyeride levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and for preventing or reducing the risk ofhaving a first or subsequent atherosclerotic disease event in mammals,particularly in humans.

Additionally, an effective amount of a compound of formula I and atherapeutically effective amount of one or more active agents selectedfrom the group consisting of: an antihyperlipidemic agent; a plasmaHDL-raising agent; an antihypercholesterolemic agent such as acholesterol biosynthesis inhibitor, for example an HMG-CoA reductaseinhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidaseinhibitor, or a squalene synthetase inhibitor (also known as squalenesynthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferaseinhibitor; probucol; nicotinic acid and the salts thereof; niacinamide;a cholesterol absorption inhibitor; a bile acid sequestrant anionexchange resin; a low density lipoprotein receptor inducer; clofibrate,fenofibrate, and gemfibrozol; vitamin B₆ and the pharmaceuticallyacceptable salts thereof; vitamin B_(12;) an anti-oxidant vitamin; abeta-blocker; an angiotensin II antagonist; an angiotensin convertingenzyme inhibitor; a platelet aggregation inhibitor; a fibrinogenreceptor antagonist; aspirin; fenfluramines, dexfenfluramines,phentiramines, β3 adrenergic receptor agonists; sulfonylureas,biguanides, α-glucosidase inhibitors, other insulin secretogogues, andinsulin can be used together for the preparation of a medicament usefulfor the above-described treatments.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Specific examples of formula I may require the use of protecting groupsto enable their successful elaboration into the desired structure.Protecting groups may be chosen with reference to Greene, T. W., et al.,Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1991.The blocking groups are readily removable, i.e., they can be removed, ifdesired, by procedures which will not cause cleavage or other disruptionof the remaining portions of the molecule. Such procedures includechemical and enzymatic hydrolysis, treatment with chemical reducing oroxidizing agents under mild conditions, treatment with fluoride ion,treatment with a transition metal catalyst and a nucleophile, andcatalytic hydrogenation.

Examples of suitable hydroxyl protecting groups are: trimethylsilyl,triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,t-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, andallyloxycarbonyl. Examples of suitable carboxyl protecting groups arebenzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl,2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl,t-butyldimethylsilyl, t-butldiphenyisilyl, 2-(trimethylsilyl)ethyl,phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyland t-butyl.

The compounds used in the method of the invention can be preparedreadily according in the following detailed examples using readilyavailable starting materials, reagents and conventional systhesisprocedures. In these reactions, it is also possible to make use ofvariants which are themselves known to those of ordinary skill in thisart, but which are not mentioned in greater detail. Additionalbackground information and further details on the preparation of thecompounds of formula XI and XII is taught in EP B-106565, the entiredisclosure of which is incorporated herein by reference.

EXAMPLE 1 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)2,3-dichlorobenzeneacetic Acid

Step A. Preparation of 2,3-dichloro-4-methoxy-acetophenone

To a suspension of AlCl₃, 80 gm, in CH₂ Cl₂, 1000 mL, was added dropwiseacetyl-chloride, 31.6 gm. The solution was cooled at -5° C. and2,3-dichloroanisole, 70.8 gm, dissolved in CH₂ Cl₂, 50 mL, was thenadded. The solution was allowed to warm to room temperature and wasstirred for 4 hours. The reaction mixture was poured on ice and stirredfor 30 minutes. The organic layer was decanted and the aqueous layer wasextracted with CH₂ Cl₂. The combined fractions were washed with brine,dried (Na₂ SO₄) and concentrated to a small volume. The addition ofhexane caused crystallization of the title compound that was filtered toyield 57.7 gm (66%), mp 73°-77° C., analysis, calculated: C, 49.34; H,3.68; Cl, 32.36; obtained: C, 49.09; H, 3.61; Cl, 32.34.

Step B: Preparation of 2,3-dichloro-4-methoxybenzene acetic acid, methylEster

To a mixture of 2,3-dichloro-4-methoxyacetophenone, 58 gm, methanol, 450mL, and 70% perchloric acid, 88 mL, cooled to 0° C., there was addedthallium trinitrate trihydrate, 117 gm. The reaction mixture was allowedto warm to room temperature and was stirred for 18 hours. The mixturewas poured in water, 700 mL, and was extracted twice with CH₂ Cl₂, 500mL. The combined organic fractions were washed successively with water,5% NaHCO₃ and with water, dried (Na₂ SO₄) and concentrated in vacuo toyield, after purification by chromatography on silica gel, the titlecompound, 50.6 gm, as an oil, readily characterized by its NMR spectrum:(ppm) (CDCl₃) 3.85 (3H, s, CH₃ O), 3.73 (2H, s, CH₂ CO), 3.68 (3H, s,CH₃ O).

Step C: Preparation of 2,3-dichloro-4-hydroxy-benzeneacetic acid, methylEster.

2,3-Dichloro-4-methoxybenzeneacetic acid, methyl ester, 46 gm, wasrefluxed for 18 hours in concentrated HBr, 350 mL. The reaction mixturewas poured in water, 1.4 L, and the solution was extracted with EtOAc,2×500 mL. The organic layers were washed with water, dried (Na₂ SO₄) andconcentrated to dryness. The residue was slurried in 20% EtOAc-hexane toyield 2,3-dichloro-4-hydroxybenzeneacetic acid, mp 189°-190° C. The acidwas stirred at room temperature in methanolic HCl, 100 mL, for 30minutes. The volatiles were removed in vacuo and the residue wasslurried in hexane, filtered and air-dried to yield 17.6 gm of the titlecompound, mp 105°-106° C., analysis, calculated: C, 45.98; H, 3.43; Cl,30.16; obtained: C, 46.10; H, 3.65; Cl, 30.31.

Step D: Preparation of2,3-dichloro-4-dimethyl-thiocarbamoyloxybenzeneacetic acid, methyl ester

Sodium hydride, 99%, 1.3 gm, was added to a solution of2,3-dichloro-4-hydroxybenzeneacetic acid, methyl ester, 11.4 gm, in DMF,100 mL. The mixture was stirred until evolution of H₂ gas subsided.Dimethylthiocarbamoyl chloride, 6.5 gm, was then added and the reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was poured in water, 200 mL, and was extracted with ether, 500mL. The ether layer was washed with water, dried (Na₂ SO₄) andconcentrated in vacuo to yield an oil that was purified bychromatography on silica gel to yield 11.7 gm of the title compound, mp87°-93° C., analysis, calculated: C, 44.73; H, 4.06; N, 4.34; S, 9.95;Cl, 22.00; obtained: C, 44.44; H, 4.15; N, 4.05; S, 9.05; Cl, 21.65.

Step E: Preparation of2,3-dichloro-4-dimethyl-carbamoylthiobenzeneacetic acid, methyl Ester

2,3 -Dichloro-4-dimethylthiocarbamoylbenzene-acetic acid, methyl ester,10.7 gm, was heated under N₂ atmosphere at 250° C. for 30 minutes. Thereaction mixture was cooled to room temperature and after a purificationby chromatography on silica gel, the title compound, 6.8 gm, wasobtained, mp 119°-122° C., analysis, calculated: C, 44.73; H, 4.06; N,4.34; S, 9.95; Cl, 22.00; obtained: C, 44.50; H, 4.21; N, 4.25; S,10.19; Cl, 22.57.

Step F: Preparation of the sodium salt of2,3-dichloro-4-mercaptobenzeneacetic acid, methyl Ester

2,3-Dichloro-4-dimethylcarbamoylthiobenzene-acetic acid, methyl ester,3.22 gm, was refluxed in methanol, 60 mL, containing sodium methoxide,855 mg, for 1 hour. The reaction mixture, containing about 10 millimolesof the sodium salt of the title compound, in 60 mL MeOH, was used assuch in Step G.

Step G: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzene-acetic acid, methyl Ester

To 30 mL of the solution obtained in Step F was added4-(3-bromopropoxy)-3-propyl-2-hydroxyacetophenone, 1.73 gm, and thereaction mixture was refluxed for 2 hours. It was then poured in waterand extracted with EtOAc. The extract was washed with water, dried (Na₂SO₄) and concentrated in vacuo. The title compound, mp 82°-85° C. wasobtained by chromatography of the residue on silica gel.

Step H: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichloro-benzeneaceticacid

The ester prepared in Step F, 964 mg, dissolved in 1N NaOH, 10 mL, andin methanol, 30 mL, was refluxed for 30 minutes. The volatiles wereevaporated in vacuo. The residue was taken up in water and the resultingsolution was acidified with 20% citric acid. The mixture was extractedwith EtOAc, the extracts were washed with water, dried (Na₂ SO₄) andconcentrated in vacuo to yield the title compound, mp 119°-122° C.

EXAMPLE 24-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticAcid

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid, methyl Ester

By following Step G of Example 1, but substituting 4-(2,3epoxypropoxy)-3-propyl-2-hydroxy- acetophenone for4-(3-bromopropoxy)-3-propyl-2-hydroxyacetophenone, the title compound,mp 85°-88° C., was obtained.

Step B:4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneaceticAcid

By following Step H of Example 1, but substituting the product of Step Aof this example for the ester of Step G of Example 1, the titlecompound, mp 151°-153° C., was obtained.

EXAMPLE 34-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneaceticacid-S-Oxide

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzene-aceticacid-S-oxide, methyl Ester

The product obtained in Step G of Example 1, 1.4 gm, in CH₂ Cl₂, 35 mL,was treated with m-chloroperbenzoic acid, 560 mg, for 15 minutes at 0°C. Ca(OH)₂, 3 gm, was added and the resulting suspension was stirred for10 minutes. The solids were filtered off and the filtrate wasconcentrated in vacuo to yield the title compound, mp 153°-155° C.

Step B: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzene-aceticacid-S-Oxide

By following Step H of Example 1, but substituting the product of Step Aof this example for the ester of Step G of Example 1, the titlecompound, mp 162°-164° C., was obtained.

EXAMPLE 44-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl-sulfonyl)-2,3-dichlorobenzeneaceticAcid

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichloro-benzeneacetic acid, methyl Ester

The product obtained in Step G of Example 1, 1.4 gm, in CH₂ Cl₂, 35 mL,was treated with m-chloroperbenzoic acid, 1.15 gm, for 2 hours at roomtemperature. Ca(OH)₂, 4 gm, was added and the resulting suspension wasstirred for 10 minutes. The solids were filtered off and the filtratewas concentrated in vacuo to yield the title compound, mp 115°-118° C.

Step B: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichloro-benzeneaceticAcid

By following Step H of Example 1, but substituting the product of Step Aof this example for the ester of Step G of Example 1, the titlecompound, mp 180°-181° C., was obtained.

EXAMPLE 54-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticacid-S-Oxide

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid-S-oxide, methyl Ester

By following Step A of Example 3, but substituting the product of Step Aof Example 2 for the ester of Step G of Example 1, the title compound,mp 149°-152° C., was obtained.

Step B: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneaceticacid-S-Oxide

By following Step H of Example 1 but substituting the product of Step Aof this example for the ester of Step G of Example 1, the titlecompound, mp 166°-170° C., was obtained.

EXAMPLE 6 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2,3-dichlorobenzeneaceticAcid

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2,3-dichlorobenzeneaceticacid, methyl Ester

By following Step A of Example 4, but substituting the product of Step Aof Example 2 for the ester from Step G of Example 1, the title compound,mp 122°-125° C., was obtained.

Step B: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2,3-dichlorobenzeneacetic Acid

By following Step H of Example 1, but substituting the product from StepA of this example for the ester of Step G of Example 1, the titlecompound, mp 181°-183° C., was obtained.

EXAMPLE 7 4-(3 -(⁴-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneacetic Acid

Step A: Preparation of 4-methoxy-2-Fluoroacetophenone

By following Step A of Example 1, but substituting m-fluoroanisole for2,3-dichloroanisole, the title compound, mp 50°-52° C., was obtained.

Step B: Preparation of 4-methoxy-2-fluorobenzene-acetic acid, methylEster

By following Step B of Example 1 but substituting4-methoxy-2-fluoroacetophenone for 2,3-dichloro-4-methoxyaceto-phenone,the title compound, bp 112°-115° C./1 Torr, was obtained.

Step C: Preparation of 4-hydroxy-2-fluorobenzene acetic acid. methylEster

By following Step C of Example I but substituting4-methoxy-2-fluorobenzeneacetic acid, methyl ester for2,3-dichloro-4-methoxybenzeneacetic acid, methyl ester,4-hydroxy-2-fluorobenzeneacetic acid was obtained as a sticky solidwhich was treated with methanolic HCI to yield the title compound asanoil. It was characterized by its NMR spectrum: (ppm) (CDCl₃) 3.70 (3H,s, CH₃ O), 3.55 (2H, s, CH₂).

Step D: Preparation of 2-fluoro-4-dimethylthio-carbamoyloxybenzeneaceticacid, methyl Ester

By following Step D of Example 1 but substituting4-hydroxy-2-fluorobenzeneacetic acid, methyl ester for4-hydroxy-2,3-dichlorobenzeneacetic acid, methyl ester, the titlecompound, mp 113°-114° C., was obtained.

Step E: Preparation of 2-fluoro-4-dimethyl-carbamoylthiobenzeneaceticacid, methyl Ester

By following Step E of Example 1 but substituting2-fluoro-4-dimethylthiocarbamoyloxy-benzeneacetic acid, methyl ester for2,3-dichloro-4-dimethylthiocarbamoyloxybenzeneacetic acid, methyl ester,the title compound, mp 79°-81° C., was obtained.

Step F: Preparation of the sodium salt of2-fluoro-4-mercaptobenzeneacetic acid, methyl Ester

By following Step F of Example 1 but substituting2-fluoro-4-dimethylcarbamoylthiobenzene-acetic acid, methyl ester for2,3-dichloro-4-dimethyl-carbamoylthiobenzeneacetic acid, methyl ester asolution of the title compound was obtained and was used as such in thefollowing Step.

Step G: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzene-aceticacid, methyl Ester

By following Step G of Example 1 but substituting the product of Step Fof this example for the product of Step F of Example 1, the titlecompound, mp 63°-65° C., was obtained.

Step H: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzene-aceticAcid

By following Step H of Example 1, but substituting the methyl ester ofStep G of this example for the methyl ester of Step G of Example 1, thetitle compound, mp 154°-156° C., was obtained.

EXAMPLE 8 Sodium Salt of4-(3-(4-Acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropylthio-2-fluorobenzeneaceticacids Monohydrate

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneacetic acid, methyl Ester

By following Step G of Example 7, but substituting4-(2,3-epoxypropoxy)-3-propyl-2-hydroxy-acetophenone for4-(3-bromopropoxy)-3-propyl-2-hydroxyacetophenone, the title compoundwas obtained as an oil. Analysis, calculated: C, 61.31; H, 6.04; F,4.21; S, 7.11; obtained: C, 61.08; H, 6.51; F, 3.93; S, 6.69.

Step B: Preparation of the sodium salt of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio-2-fluorobenzeneaceticacid, Monohydrate

By following Step H of Example 7, but substituting the product of Step Aof this example for the ester of Step G of Example 7, the correspondingacid of the title compound was obtained as an oil. It was treated withone equivalent of sodium hydroxide in water to yield, after evaporationof the water, the title compound, mp 75°-83° C., analysis, calculated:C, 55.45; H, 5.50; F, 3.98; S, 6.73; obtained: C, 55.55; H, 5.56; F,4.71; S, 6.99.

EXAMPLE 9 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2-fluorobenzeneaceticacid-S-Oxide

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2-fluoro-benzeneaceticacid-S-oxide, methyl Ester

By following Step A of Example 3, but substituting the title compound ofStep A of Example 8 for the title compound of Step G of Example 1, thetitle compound is obtained.

Step B: Preparation4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2-fluoro-benzeneaceticacid-S-Oxide

By following Step H of Example 2, but substituting the product of Step Aof this example for the ester of Step G of Example 1, the title compoundis obtained.

EXAMPLE 10 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2-fluorobenzeneaceticacid; and 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-1-propenyl-sulfonyl)-2-fluorobenzeneacetic Acid

Step A: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneaceticacid, methyl Ester

By following Step A of Example 4, but substituting the product of Step Aof Example 8 for the title compound of Step G of Example 1, the titlecompound, mp 118°-119° C., was obtained.

Step B: Preparation of4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneaceticacid; and 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-propenylsulfonyl)-2-fluorobenzeneacetic Acid

By following Step H of Example 1, but substituting the product of Step Aof this example for the ester of Step G of Example 1, a mixture wasobtained. After recrystallization from diethyl ether,4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneaceticacid, mp 119°-120° C., was obtained. The mother liquors were purified bychromatography on silica gel to yield4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-propenyl-sulfonyl)-2-fluoro-benzeneacetic acid, mp 249°-251° C.

BIOLOGICAL ASSAYS

The ability of compounds of the present invention to enhance the insulinactivation of ¹⁴ C-glucose incorporation into glycogen in white adiposetissue (WAT) was determined by the following assay.

Biological Assays

I. White Adipose Tissue in vitro Assay

The ability of compounds of the present invention to enhance the insulinactivation of ¹⁴ C-glucose incorporation into glycogen in white adiposetissue (WAT) was determined by the following assay.

This assay measures the efficacy of the instant compounds to enhance theinsulin activation of ¹⁴ C-glucose incorporation into glycogen in whiteadipose tissue (WAT) in a 5 hour completely in vitro system. Allprocedures are performed in medium 199 containing 1% bovine serumalbumen, 5 mM HEPES, and antibiotic (100 units/ml penicillin, 100 μg/mlstreptomycin sulfate, 0.25 μg/ml amphotericin B), hereafter calledculture medium. Epididymol fat pads are minced with scissors into smallfragments , approximately 1 mm in diameter. Minced WAT fragments (100mg) are incubated in a total volume of 0.9 ml culture medium containing1 mU/ml insulin and test compound in tissue culture incubator at 37° C.with 5% CO₂ with orbital shaking for 3 hours. ¹⁴ C-labeled glucose isadded and incubation continued for 2 hours. Tubes are centrifuged at lowspeed, infranatant is removed and 1M NaOH is added. Incubation ofalkali-treated WAT for 10 minutes at 60° C. solubilizes tissue.Resulting tissue hydrolyzate is applied to Whatman filter paper stripswhich are then rinsed in 66% ethanol followed by 100% acetone whichremoves unincorporated ¹⁴ C-glucose from bound ¹⁴ C-glycogen. The driedpaper is then incubated in solution of amyloglucosidase to cleaveglycogen into glucose. Scintillation fluid is added and samples arecounted for ¹⁴ C activity. Test compounds that resulted in ¹⁴ C activitysubstantially above incubations with insulin alone are considered activeinsulin-enhancing agents. Active compounds were titrated to determinethe compound concentration which resulted in 50% of maximum enhancementof insulin activation and were termed EC₅₀ values. EC₅₀ values for theinstant compounds were found to be 50 μM or less, preferably 5.0 to0.0001 μM or less.

II. PPAR Receptor Binding and/or Transactivation Assays

Compounds of the instant invention which are useful for the abovediscussed treatments can be identified and/or characterized by employingthe PPAR δ, and y binding assays and/or PPAR δ, PPAR α and PPARγtransactivation assays. The assays are useful in predicting orquantitating in vivo effects having to do with the control or modulationof glucose, free fatty acid, triglyceride, insulin or cholesterol. Toevaluate IC₅₀ or EC₅₀, values the compounds were titrated in theappropriate assay using different concentrations of the compound to betested. To obtain the appropriate values (%Inhibition-IC₅₀, or%Activation-EC₅₀), the data resulting from the assays were then analyzedby determining the best fit of a 4 parameter function to the data usingthe Levenberg-Marquardt non-linear fitting algorithm in Kaleidagraph(Synergy Software, Reading, Pa.). The human nuclear receptor cDNA forPPARδ (hPPARδ) has been cloned from a human osteosarcoma cell cDNAlibrary and is fully described in A. Schmidt et al., MolecularEndocrinology, 6:1634-1641 (1992), herein incorporated by reference inits entirety. See A. Elbrecht et al., Biochem. and Biophy. Res. Comm.224:431-437 (1996) and T. Sher et al., Biochem. 32:5598-5604 (1993) fora description of the human nuclear receptor gene PPARγ and α.

The hPPARδ binding assay comprises the steps of:

(a) preparing multiple test samples by incubating separate aliquots ofthe receptor hPPARδ with a test compound in TEGM containing 5-10% COS-1cell cytoplasmic lysate and 2.5 nM labeled ( ³ H₂ !Compound D, 17Ci/mmole) for a minimum of 12 hours, and preferably for about 16 hours,at 4 ° C., wherein the concentration of the test compound in each testsample is different, and preparing a control sample by incubating afurther separate aliquot of the receptor hPPARδ under the sameconditions but without the test compound; then

(b) removing unbound ligand by adding dextran/gelatin-coated charcoal toeach sample while maintaining the samples at 4 ° C. and allowing atleast 10 minutes to pass, then

(c) subjecting each of the test samples and the control sample from step(b) to centrifugation at 4 ° C. until the charcoal is pelleted; then

(d) counting a portion of the supernatant fraction of each of the testsamples and the control sample from step (c) in a liquid scintillationcounter and analyzing the results to determine the IC₅₀ of the testcompound.

In the hPPARδ binding assay, preferably at least four test samples ofvarying concentrations of a single test compound are prepared in orderto determine the IC₅₀.

The hPPARδ transactivation assay comprises the steps of:

(a) seeding an hPPARδ/GR stable CHO-K1 cell line into alpha MEMcontaining 10% FCS, 10 mM HEPES, and 500 mg/ml G418 at 37° C. in anatmosphere of 10% CO₂ in air,

(b) incubating the cells from step (a) for 16 to 48 hours, preferablyabout 20 hours, at 37° C. in an atmosphere of 10% CO₂ in air;

(c) washing the cells from step (b) with alpha MEM;

(d) preparing multiple test cell groups by incubating separate groups ofthe cells from step (c) with the test compound in alpha MEM containing5% charcoal stripped FCS, 10 mM HEPES, and 500 mg/ml G418, for 24 to 48hours, preferably about 24 hours, at 37° C. in an atmosphere of 10% CO₂in air, wherein the concentration of the test compound in each test cellgroup is different, and preparing a control cell group by incubating afurther separate group of the cells from step (c) under the sameconditions but without the test compound; then

(e) preparing cell lysates from each of the test cell groups and thecontrol cell group of step (d) using an aqueous detergent lysis buffer,and

(f) measuring the luciferase activity of the test cell groups and thecontrol cell group of step (e) and analyzing the results to determinethe EC₅₀ of the test compound.

In the hPPARδ transactivation assay, preferably at least four test cellgroups of varying concentrations of a single test compound are preparedin order to determine the EC₅₀.

Particular terms and abbreviations used herein are defined as follows:gst is glutathione-S-transferase; EDTA is ethylenediamine-tetraaceticacid; HEPES is N- 2-hydroxyethyl!-piperazine-N'- 2-ethanesulfonic acid!;FCS is fetal calf serum; Lipofectamine is a 3:1 (w/w) liposomeformulation of the polycationic lipid 2,3-dioleyloxy-N-2(spermine-carboxamido)ethyl!-N,N-dimethyl- 1-propanaminium-trifluoroacetate and the neutral lipid dioleoylphosphatidylethanolamine in water; G418 is geneticin; MEM is MinimumEssential Medium; Opti MEM 1 Reduced-Serum Medium is an aqueouscomposition containing HEPES buffer, 2400 mg/L sodium bicarbonate,hypoxanthine, thymidine, sodium pyruvate, L-glutamine, trace elements,growth factors, and phenol red reduced to 1.1 mg/L; Luciferase AssayReagent (in re-constituted form) is an aqueous composition containing 20mM tricine, 1.07 mM (MgCO₃)₄ Mg(OH)₂.5H₂ O, 2.67 mM MgSO₄, 0.1 mM EDTA,33.3 mM DTT, 270 μM coenzyme A, 470 μM luciferin, 530 μM ATP, having afinal pH of 7.8.

AD-5075 has the following structure: ##STR14##

Opti MEM 1 Reduced-Serum Medium, alpha MEM, G418, and Lipofectamine arecommercially available from GibcoBRL Life Technologies, Gaithersburg,Md. Alpha MEM is an aqueous composition having the following components:

    ______________________________________                                                           mg/L                                                       ______________________________________                                        Component: Inorganic Salts                                                    CaCl.sub.2 (anhyd.)                                                                              200.00                                                     CaCl.sub.2.2H.sub.2 O                                                                            --                                                         KCl                400.00                                                     MgSO.sub.4 (anhyd.)                                                                              97.67                                                      MgSO.sub.4.7H.sub.2 O                                                                            --                                                         NaCl               6800.00                                                    NaHCO.sub.3        2200.00                                                    NaH.sub.2 PO.sub.4.H.sub.2 O                                                                     140.00                                                     NaH.sub.2 PO.sub.4.2H.sub.2 O                                                                    --                                                         Other Components:                                                             D-Glucose          1000.00                                                    Lipoic Acid        0.20                                                       Phenol Red         10.00                                                      Sodium Pyruvate    110.00                                                     Amino Acids:                                                                  L-Alanine          25.00                                                      L-Arginine.HCl     126.00                                                     L-Asparagine.H.sub.2 O                                                                           50.00                                                      L-Aspartic Acid    30.00                                                      L-Cystine          --                                                         L-Cystine.2HCl     31.00                                                      L-Cysteine HCl     --                                                         L-Cysteine HCl.H.sub.2 O                                                                         100.00                                                     L-Glutamic Acid    75.00                                                      L-Glutamine        292.00                                                     L-Alanyl-L-Glutamine                                                                             --                                                         Glycine            50.00                                                      L-Histidine HCl.H.sub.2 O                                                                        42.00                                                      L-Isoleucine       52.00                                                      L-Leucine          52.00                                                      L-Lysine.HCl       73.00                                                      L-Methionine       15.00                                                      L-Phenylalanine    32.00                                                      L-Proline          40.00                                                      L-Serine           25.00                                                      L-Threonine        48.00                                                      L-Tryptophan       10.00                                                      L-Tyrosine         --                                                         L-Tyrosine (disodium salt)                                                                       52.00                                                      L-Valine           46.00                                                      Vitamins:                                                                     L-Ascorbic acid    50.00                                                      Biotin             0.10                                                       D-Ca Pantothenate  1.00                                                       Choline Chloride   1.00                                                       Folic acid         1.00                                                       i-Inositol         2.00                                                       Niacinamide        1.00                                                       Pyridoxal HCl      1.00                                                       Riboflavin         0.10                                                       Thiamine HCl       1.00                                                       VitaminB.sub.12    1.40                                                       Ribonucleosides                                                               Adenosine          10.00                                                      Cytidine           10.00                                                      Guanosine          10.00                                                      Uridine            10.00                                                      Deoxyribonucleosides                                                          2' Deoxyadenosine  10.00                                                      2' Deoxycytidine HCl                                                                             11.00                                                      2' Deoxyguanosine  10.00                                                      Thymidine          10.00                                                      ______________________________________                                    

The instant compounds, which are useful for treating the above discusseddisease states, will preferably have IC₅₀ values at one, two or all ofthe PPAR (PPARγ, PPARδ or PPARα) receptor cites of equal to or less than10 μM binding assay, and an EC₅₀ equal to or less than 10 μM in thetransactivation assay. Preferably, an IC₅₀ of 100 nM in the bindingassay, and an EC₅₀ equal to or less than 100 nM in the transactivationassay. More preferably, the instant compounds have an IC₅₀ equal to orless than 50 nM in the binding assay, and an EC₅₀ equal to or less than50 nM in the transactivation assay. Most preferably, the instantcompounds have an IC₅₀ equal to or less than 10 nM in the binding assay,and an EC₅₀ equal to or less than 10 nM in the transactivation assay.

PPAR Receptor Binding Assay

A. Preparation of Human PPARγ2 and δ

Human PPARγ2 and PPARδ, independently, were prepared as gst-fusionproteins in E. coli. The full length human cDNA for PPARγ2 and PPARδwere subcloned into the PGEX-2T and PGEX-KT, respectively, expressionvector (Pharmacia). E. coli containing the plasmid were grown, induced,and then harvested by centrifugation. The resuspended pellet was brokenin a French press and debris was removed by centrifugation at 12,000×g.Receptors were purified from the supernatant by affinity chromatographyon glutathione sepharose. After application to the column, and 1 wash,receptor was eluted with glutathione. Glycerol was added to stabilizethe receptor and aliquots were frozen at -80 ° C. for later use.

B. ³ H!AD-5075 and Example 11 Displacement Assay for PPARγ2 and PPARδ,Respectively

For each assay, an aliquot of receptor (1:1000-1:3000 dilution) wasincubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μl/100ml β-mercaptoethanol, 10 nM Na molybdate, 1 mM dithiothreitol, 5 μg/mlaprotinin, 2 μg/ml leupeptin, 2 μg/ml benzamide and 0.5 mM PMSF)containing 5-10% COS-1 cell cytoplasmic lysate and 10 nM labeledthiazolidinedione ( ³ H₂ !AD-5075, 21 Ci/mmole), ±test compoundcompound, ³ H₂ !Example 11, 17 Ci/mmole), ±test compound, respectively.Assays were incubated for ˜16 h at 4 ° C. in a final volume of 300 μl.Unbound ligand was removed by addition of 200 μl dextran/gelatin-coatedcharcoal, on ice, for ˜10 minutes. After centrifugation at 3000 rpm for10 min at 4° C., 200 μl of the supernatant fraction was counted in aliquid scintillation counter. In this assay the KD for AD-5075 andExample 11 is 1 nM, respectively.

PPAR Receptor Transactivation Assay

A. Activation of hPPARγ and hPPARδMethods

1. Plasmids

The chimeric receptor expression constructs, pSG5-hPPARγ2/GR andpSG5-hPPARδ/GR, were prepared by inserting the DNA binding domain of themurine glucocorticoid receptor adjacent to the ligand binding domain ofhPPARyγ or hPPARδ. These vectors were kindly provided by Dr. AzrielSchmidt (MRL). The glucocorticoid receptor -responsive reporter vector,pMMTV/luc/neo, contains the murine mammary tumour virus (MMTV) promoteradjacent to the luciferase gene (luc) and the neomycin resistance gene(neo). It was constructed from pMMTV/luc which was provided by Dr.Azriel Schmidt (Merck Research Laboratories). Prior to transfection intoCHO-K1 cells, pSG5-hPPARγ2/GR and pSG5-hPPARδ/GR were linearized withXba I. pMMTV/luc/neo DNA was cut with Pvu I. Wild type receptorconstructs, pSG5-hPPARγ2, pSG5-hPPARδ and pSG5-hPPARα were prepared byinserting the full-length hPPARγ2, hPPARδand PPARα cDNAs adjacent to theSV40 promoter in pSG5. The PPAR-responsive reporter construct,pPPRE-luc, contained 3 copies of a generic PPRE placed adjacent to thethymidine kinase minimal promoter and the luciferase reporter gene. Thetransfection control vector, pCMV-lacZ, contains the galactosidase Zgene under the regulation of the cytomegalovirus promoter.

2. Production of Stable Cell Lines

CHO-K1 cells were seeded overnight at 6×10⁵ cells /60 mm dish in alphaMinimum Essential Medium (MEM) containing 10% fetal calf serum (FCS), 10mM HEPES, 100 units/ml PenicillinG and 100 μug/ml Streptomycin sulfateat 37° C. in an atmosphere of 10% CO₂ in air. The cells were washed oncewith OptiMEM 1 Reduced-Serum Medium and then cotransfected with 4.5 μgof pSG5-hPPARγ2 /GR or pSG5-hPPARδ/GR expression vector and 0.5 μg ofpMMTV/luc/neo in the presence of 100 μg Lipofectamine (GIBCO BRL)according to the instructions of the manufacturer. Transfection mediumwas removed 2 h later and replaced with growth medium. After beingincubated for 3 days, cells were subcultured by diluting the cellsuspension 1/1250 and 1/6250 and placing the cells in a 100 mm culturedish. Selection of the stable cell lines was initiated the next day byadding 500 μg/ml G418 to the medium. Cells were routinely fed with theselection media for 1 month at which time 120 colonies were picked andtransferred to 24 well culture plates. Ten days later, confluentcolonies were transferred to 6 well plates to maintain stocks and to 96well plates to assay for luciferase activity. Positive clones werecharacterized and validated by titrating 4 known agonists on each clone.Two clones, g2B2P2D9 and d2A5P2G3, were selected for screening purposes.

B. hPPAR/GR Transactivation Screens in Stably Transfected CHO-K1 Cells

The hPPARγ2/GR and hPPARδ/GR stable CHO-K1 cell lines were seeded at1×10⁴ cells/well in 96 well cell culture plates in alpha MEM containing10% FCS, 10 mM HEPES, and 500 mg/ml G418 at 37° C. in an atmosphere of10% CO₂ in air. After a 20 hour incubation, cells were washed once withalpha MEM and then incubated in an atmosphere of 10% CO₂ in air in alphaMEM containing 5% charcoal stripped FCS, 10 mM HEPES, and 500 mg/mlG418. The cells were incubated for 24 hours in the absence of testcompound or in the presence of a range of concentrations of testcompound. Cell lysates were prepared from washed cells using ReporterLysis Buffer (Promega) according to the manufacturer's directions.Luciferase activity in cell extracts was determined using LuciferaseAssay Reagent buffer (Promega) in a ML3000 luminometer (DynatechLaboratories).

Transactivation Wild-Type Assay

A. Characterization of Ligand Activity on Wild-Type hPPARγ, hPPARδ andhPPARα.

COS-1 cells were seeded at 0.5×10⁵ cells/dish into 24 well plates inDulbecco's modified Eagle medium (high glucose) containing 10% charcoalstripped fetal calf serum, nonessential amino acids, 100 units/mlPenicillin G and 100 μg/ml Streptomycin sulfate at 37° C. in ahumidified atmosphere of 10% CO₂. After 24 hours, transfections wereperformed with Lipofectamine (Gibco-BRL, Gaithersburg, Md.) according tothe instructions of the manufacturer. In general, for transactivationexperiments, transfection mixes contained 0.15 mg of hPPARγ2 hPPARα orhPPARδ expression vector, 0.15 mg of reporter vector pPPRE-luc and 0.001mg of pCMV-lacZ as an internal control of transfection efficiency.Compounds demonstrating significant agonist activity in the aboveprimary screen were further characterized by incubation with transfectedcells for 48h across a range of concentrations. Luciferase activity wasdetermined as described above.

In a similar manner, hPPARγ1 cDNA can be used in place of hPPARγ2 cDNAin the methods described in Example 5 to make the wild type receptorconstruct, pSG5-hPPARγ1.

III.In vivo Studies

Methods

db/db Mice are obese, highly insulin resistant animals. The db locus hasbeen shown to code for the leptin receptor. These animals aresubstantially hypertriglyceridemic and hyperglycemic.

Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor,Me.) were housed 5/cage and allowed ad lib. access to ground Purinarodent chow and water. The animals, and their food, were weighed every 2days and were dosed daily by gavage with vehicle (0.5%carboxymethylcellulose) ±test compound at the indicated dose. Drugsuspensions were prepared daily. Plasma glucose, Cholesterol andtriglyceride concentrations were determined from blood obtained by tailbleeds at 3-5 day intervals during the study period. Glucose,cholesterol and triglyceride, determinations were performed on aBoehringer Mannheim Hitachi 911 automatic analyzer (Boehringer Mannheim,Indianapolis, Ind.) using heparinized plasma diluted 1:5, or 1:6 (v/v)with normal saline. Lean animals were age-matched heterozygous micemaintained in the same manner. The instant compounds were found to lowertriglyceride and glucose levels at a dose of about 100mg/kg, preferablya dose of about 10-50 mg/kg, when administered by oral gavage daily fora period of at least 5 days.

Lipoprotein analysis was performed on either serum, or EDTA treatedplasma obtained by heart puncture from anesthetized animals at the endof the study. Apolipoprotein concentrations were determined by ELISA,and cholesterol particles were analyzed by FPLC, precipitation, orultracentrifugation. Total liver RNA was prepared from tissue that hadbeen frozen on liquid nitrogen at the time of euthanasia. ApolipoproteinmRNA was analyzed on Northern Blots using specific probes for mouse orrat proteins.

What is claimed is:
 1. A method for the treatment or prevention ofdiabetes which comprises administering to a diabetic patient apharmaceutically effective amount of a compound of formula XI or XII:##STR15## or a pharmaceutically acceptable salt or acid addition saltthereof, wherein:each R is independently H, OH, alkyl of 1 to 6 carbonatoms which may be straight chain or branched; alkenyl of 2 to 6 carbonatoms which may be straight chain or branched; trifluoromethyl; alkoxyof 1 to 6 carbon atoms which may be straight chain or branched; SH;thioalkyl of 1 to 6 carbon atoms which may be straight chain orbranched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms orby halogen; benzyl; phenethyl; halogen, amino; N(R₄)₂ wherein R₄ is H oralkyl of 1 to 6 carbon atoms which may be straight chain or branched;COOR₄ ; CH₂ OR₄ ; formyl; CN; trifluoromethylthio; or nitro; each R' isindependently R₄ ; OR₄ ; COOR₄ ; N(R₄)₂ ; SR₄ ; CH₂ OR₄ ; CHO; ortogether R' and R' are O; CH₂ ; or ##STR16## Y' is sulfur,sulfoxide,sulfone; ##STR17## R₁₁ is H, alkyl of 1-4 carbon atoms whichmay be straight chain or branched; alkanoyl of 1-4 carbon atoms whichmay be straight chain or branched; phenylsulfonyl; tosyl; NR₁₂ whereinR₁₂ is H, alkyl of 1-4 carbon atoms which may be straight chain orbranched; or ##STR18## wherein R₁₃ is alkyl of 1-4 carbon atoms whichmay be straight chain or branched, alkoxy of 1-4 carbon atoms which maybe straight chain or branched; N--CN, CH₂, or C═O; Y is Y' and oxygen;each R₁ is independently hydrogen or alkyl of 1-3 carbon atoms; each mis independently an integer from 0-6; R₂ is ##STR19## each R₆ isindependently H or alkyl of 1-4 carbons; each R₇ is independently H, OH,or alkyl of 1-4 carbons; each R₈ is independently H, or alkyl of 1-4carbons, and is absent when a triple bond is present; R₅ is COOR₄ ; CH₂OH; CHO; tetrazole; NHSO₂ R₁₄ ; hydroxymethylketone; CN; CON(R₇)₂ ; amonocyclic or bicyclic heterocyclic ring containing an acidic hydroxylgroup; or COOR₁₅ where R₁₅ is ##STR20## wherein each s is independently0-3; R₁₆ isA) a monocyclic or bicyclic heterocyclic radical containingfrom 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatomsselected from N and S with at least one being N, and with each ring inthe heterocyclic radical being formed of 5 or 6 atoms, or B) the radicalW--R₁₇ wherein W is O, S or NH and R₁₇ contains up to 21 carbon atomsand is (1) a hydrocarbon radical or (2) an acyl radical of an organicacyclic or monocyclic carboxylic acid containing not more than 1heteroatom in the ring; R₁₄ is OH, alkyl or alkoxy of 1 to 6 carbonatoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms; r an q areeach independently 0-20 provided that the total of r and q does notexceed 20; p is 0 or 1; R₃ is alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; or alkenyl of 3 to 6 carbon atoms which maybe straight chain or branched as illustrated in formulas IV and V; R₉ isalkyl of 1 to 6 carbon atoms which may be straight chain or branched;alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;or (CH₂)_(r) R₅ ; and R₁₀ is H; alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; ##STR21## or R₄ OCH₂ --.
 2. A methodaccording to claim 1 wherein the compound is Y is oxygen and Y' issulfur, sulfoxide, sulfone, amino or cyanamido.
 3. A method according toclaim 1 wherein each m is
 1. 4. A method according to claim 1 whereinthe compoundis4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichlorobenzeneacetic acid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester; 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneaceticacid-S-oxide and its methyl ester; 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2,3-dichlorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneaceticacid and its methyl ester; Sodium Salt of4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneaceticacid, monohydrate and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2-fluorobenzeneaceticacid-S-oxide and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneaceticacid; and 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)- 1-propenylsulfonyl)-2-fluorobenzeneacetic acid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-3-fluorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzeneaceticacid and its methyl ester; 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio-3-chlorobenzeneacetic acid and itsmethyl ester; 4-(3-(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio)-3-chlorobenzeneacetic acid-S-oxide and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-chlorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneaceticacid-S-oxide and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneaceticacid and its methyl ester; 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-thio)benzeneacetic acid andits methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-benzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-propylthio)-benzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-benzeneaceticacid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoic acid and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoicacid and its methyl ester; 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acidand its methyl ester; 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3 -fluorobenzoic acid-S-oxide,methyl ester and its methyl ester;4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-fluorobenzoicacid and its methyl ester; and4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-cyanamido)-benzeneaceticacid and its methyl ester.
 5. A method for the treatment or preventionof diabetes which comprises administering to a diabetic patient aneffective amount of a compound of claim 1 in combination with asulfonylurea, fibrate, HMG-CoA reductase inhibitor, beta-sitosterolinhibitor, cholesterol acyltransferase inhibitor, biguanides,cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid,fibrinogen receptor antagonists, aspirin, α-glucosidase inhibitors,insulin secretogogue or insulin.
 6. A method for treating obesity whichcomprises administering to a patient in need thereof an effective amountof a compound of formula XI or XII: ##STR22## or a pharmaceuticallyacceptable salt or acid addition salt thereof, wherein:each R isindependently H, OH, alkyl of 1 to 6 carbon atoms which may be straightchain or branched; alkenyl of 2 to 6 carbon atoms which may be straightchain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms whichmay be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atomswhich may be straight chain or branched; phenyl; phenyl substituted byalkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen,amino; N(R₄)₂ wherein R₄ is H or alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; COOR₄ ; CH₂ OR₄ ; formyl; CN;trifluoromethylthio; or nitro; each R' is independently R₄ ; OR₄ ; COOR₄; N(R₄)₂ ; SR₄ ; CH₂ OR₄ ; CHO; or together R' and R' are O; CH₂ ; or##STR23## Y' is sulfur, sulfoxide,sulfone; ##STR24## R₁₁ is H, alkyl of1-4 carbon atoms which may be straight chain or branched; alkanoyl of1-4 carbon atoms which may be straight chain or branched;phenylsulfonyl; tosyl; NR₁₂ wherein R₁₂ is H, alkyl of 1-4 carbon atomswhich may be straight chain or branched; or ##STR25## wherein R₁₃ isalkyl of 1-4 carbon atoms which may be straight chain or branched,alkoxy of 1-4 carbon atoms which may be straight chain or branched;N--CN, CH₂, or C═O; Y is Y' and oxygen; each R₁ is independentlyhydrogen or alkyl of 1-3 carbon atoms; each m is independently aninteger from 0-6; R₂ is ##STR26## each R₆ is independently H or alkyl of1-4 carbons; each R₇ is independently H, OH, or alkyl of 1-4 carbons;each R₈ is independently H, or alkyl of 1-4 carbons, and is absent whena triple bond is present; R₅ is COOR₄ ; CH₂ OH; CHO; tetrazole; NHSO₂R₁₄ ; hydroxymethylketone; CN; CON(R₇)₂ ; a monocyclic or bicyclicheterocyclic ring containing an acidic hydroxyl group; or COOR₁₅ whereR₁₅ is ##STR27## wherein each s is independently 0-3; R₁₆ isA) amonocyclic or bicyclic heterocyclic radical containing from 3 to 12nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N andS with at least one being N, and with each ring in the heterocyclicradical being formed of 5 or 6 atoms, or B) the radical W--R₁₇ wherein Wis O, S or NH and R₁₇ contains up to 21 carbon atoms and is (1) ahydrocarbon radical or (2) an acyl radical of an organic acyclic ormonocyclic carboxylic acid containing not more than 1 heteroatom in thering; R₁₄ is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl orphenyl substituted by alkyl or alkoxy groups of I to 3 carbon atoms,halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of I to 6 carbonatoms or perfluoroalkyl of 1 to 4 carbon atoms; r an q are eachindependently 0-20 provided that the total of r and q does not exceed20; p is 0 or 1; R₃ is alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; or alkenyl of 3 to 6 carbon atoms which maybe straight chain or branched as illustrated in formulas IV and V; R₉ isalkyl of 1 to 6 carbon atoms which may be straight chain or branched;alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;or (CH₂)_(r) R₅ ; and R₁₀ is H; alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; ##STR28## or R₄ OCH₂ --.
 7. A methodaccording to claim 6 in combination with a fenfluramine,dexfenfluramine, phentiramine or δ3 adrenergic receptor agonist.
 8. Amethod for lowering triglyceride levels which comprises administering toa patient needing lower triglyceride an effective amount of a compoundof formula XI or XII: ##STR29## or a pharmaceutically acceptable salt oracid addition salt thereof, wherein:each R is independently H, OH, alkylof 1 to 6 carbon atoms which may be straight chain or branched; alkenylof 2 to 6 carbon atoms which may be straight chain or branched;trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straightchain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may bestraight chain or branched; phenyl; phenyl substituted by alkyl of 1 to3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R₄)₂wherein R₄ is H or alkyl of 1 to 6 carbon atoms which may be straightchain or branched; COOR₄ ; CH₂ OR₄ ; formyl; CN; trifluoromethylthio; ornitro; each R' is independently R₄ ; OR₄ ; COOR₄ ; N(R₄)₂ ; SR₄ ; CH₂OR₄ ; CHO; or together R' and R' are O; CH₂ ; or ##STR30## Y' is sulfur,sulfoxide,sulfone; ##STR31## R₁₁ is H, alkyl of 1-4 carbon atoms whichmay be straight chain or branched; alkanoyl of 1-4 carbon atoms whichmay be straight chain or branched; phenylsulfonyl; tosyl; NR₁₂ whereinR₁₂ is H, alkyl of 1-4 carbon atoms which may be straight chain orbranched; or ##STR32## wherein R ₁₃ is alkyl of 1-4 carbon atoms whichmay be straight chain or branched, alkoxy of 1-4 carbon atoms which maybe straight chain or branched; N--CN, CH₂, or C═O; Y is Y' and oxygen;each R₁ is independently hydrogen or alkyl of 1-3 carbon atoms; each mis independently an integer from 0-6; R₂ is ##STR33## each R₆ isindependently H or alkyl of 1-4 carbons; each R₇ is independently H, OH,or alkyl of 1-4 carbons; each R₈ is independently H, or alkyl of 1-4carbons, and is absent when a triple bond is present; R₅ is COOR₄ ; CH₂OH; CHO; tetrazole; NHSO₂ R₁₄ ; hydroxymethylketone; CN; CON(R₇)₂ ; amonocyclic or bicyclic heterocyclic ring containing an acidic hydroxylgroup; or COOR₁₅ where R₁₅ is ##STR34## wherein each s is independently0-3; R₁₆ isA) a monocyclic or bicyclic heterocyclic radical containingfrom 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatomsselected from N and S with at least one being N, and with each ring inthe heterocyclic radical being formed of 5 or 6 atoms, or B) the radicalW--R₁₇ wherein W is O, S or NH and R₁₇ contains up to 21 carbon atomsand is (1) a hydrocarbon radical or (2) an acyl radical of an organicacyclic or monocyclic carboxylic acid containing not more than 1heteroatom in the ring; R14 is OH, alkyl or alkoxy of 1 to 6 carbonatoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms; r an q areeach independently 0-20 provided that the total of r and q does notexceed 20; p is 0 or 1; R₃ is alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; or alkenyl of 3 to 6 carbon atoms which maybe straight chain or branched as illustrated in formulas IV and V; R₉ isalkyl of 1 to 6 carbon atoms which may be straight chain or branched;alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;or (CH₂)_(r) R₅ ; and R₁₀ is H; alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; ##STR35## or R₄ OCH₂ --.
 9. A method forhalting, preventing or reducing the risk of developing atherosclerosisand related diseae events in a patient in need of such treatment,comprising the administration of a pharmaceutically effective amount ofa compound of formula XI or XII: ##STR36## or a pharmaceuticallyacceptable salt or acid addition salt thereof, wherein:each R isindependently H, OH, alkyl of 1 to 6 carbon atoms which may be straightchain or branched; alkenyl of 2 to 6 carbon atoms which may be straightchain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms whichmay be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atomswhich may be straight chain or branched; phenyl; phenyl substituted byalkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen,amino; N(R₄)₂ wherein R₄ is H or alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; COOR₄ ; CH₂ OR₄ ; formyl; CN;trifluoromethylthio; or nitro; each R' is independently R₄ ; OR₄ ; COOR₄; N(R₄)₂ ; SR₄ ; CH₂ OR₄ ; CHO; or together R' and R' are O; CH₂ ; or##STR37## Y' is sulfur, sulfoxide,sulfone; ##STR38## R₁ is H, alkyl of1-4 carbon atoms which may be straight chain or branched; alkanoyl of1-4 carbon atoms which may be straight chain or branched;phenylsulfonyl; tosyl; NR₁₂ wherein R₁₂ is H, alkyl of 1-4 carbon atomswhich may be straight chain or branched; or ##STR39## wherein R₁₃ isalkyl of 1-4 carbon atoms which may be straight chain or branched,alkoxy of 1-4 carbon atoms which may be straight chain or branched;N--CN, CH₂, or C═O; Y is Y' and oxygen; each R₁ is independentlyhydrogen or alkyl of 1-3 carbon atoms; each m is independently aninteger from 0-6; R₂ is ##STR40## each R₆ is independently H or atkyl of1-4 carbons; each R₇ is independently H, OH, or alkyl of 1-4 carbons;each R₈ is independently H, or alkyl of 1-4 carbons, and is absent whena triple bond is present; R₅ is COOR₄ ; CH₂ OH; CHO; tetrazole; NHSO₂R₁₄ ; hydroxymethylketone; CN; CON(R₇)₂ ; a monocyclic or bicyclicheterocyclic ring containing an acidic hydroxyl group; or COOR₁₅ whereR₁₅ is ##STR41## wherein each s is independently 0-3; R₁₆ isA) amonocyclic or bicyclic heterocyclic radical containing from 3 to 12nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N andS with at least one being N, and with each ring in the heterocyclicradical being formed of 5 or 6 atoms, or B) the radical W--R₁₇ wherein Wis O, S or NH and R₁₇ contains up to 21 carbon atoms and is (1) ahydrocarbon radical or (2) an acyl radical of an organic acyclic ormonocyclic carboxylic acid containing not more than 1 heteroatom in thering; R₁₄ is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl orphenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms,halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbonatoms or perfluoroalkyl of 1 to 4 carbon atoms; r an q are eachindependently 0-20 provided that the total of r and q does not exceed20; p is 0 or 1; R₃ is alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; or alkenyl of 3 to 6 carbon atoms which maybe straight chain or branched as illustrated in formulas IV and V; R₉ isalkyl of 1 to 6 carbon atoms which may be straight chain or branched;alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;or (CH₂)_(r) R₅ ; and R₁₀ is H; alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; ##STR42## or R₄ OCH₂ --.
 10. A methodaccording to claim 9 wherein the compound has an IC₅₀ equal to or lessthan 10 μM in the hPPARδbinding assay and an EC₅₀ equal to or less than10 μM in the hPPARδtransactivation assay.
 11. The method of claim 10wherein the compound has an IC₅₀ equal to or less than 100 nM in thehPPARδ binding assay and an EC₅₀ equal to or less than 100 nM in thehPPARδ transactivation assay.
 12. The method of claim 11 wherein thecompound has an IC₅₀ equal to or less than 50 nM in the hPPARδ bindingassay and an EC₅₀ equal to or less than 50 nM in the hPPARδtransactivation assay.
 13. The method of claim 12 wherein the compoundhas an IC₅₀ equal to or less than 10 nM in the hPPARδ binding assay andan EC₅₀ equal to or less than 10 nM in the hPPARδ transactivation assay.14. A method for raising high densisty lipoprotein plasma levels in apatient in need of such treatment, comprising the administration of apharmaceutically effective amount of a compound of formula XI or XII:##STR43## or a pharmaceutically acceptable salt or acid addition saltthereof, wherein:each R is independently H, OH, alkyl of 1 to 6 carbonatoms which may be straight chain or branched; alkenyl of 2 to 6 carbonatoms which may be straight chain or branched; trifluoromethyl; alkoxyof 1 to 6 carbon atoms which may be straight chain or branched; SH;thioalkyl of 1 to 6 carbon atoms which may be straight chain orbranched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms orby halogen; benzyl; phenethyl; halogen, amino; N(R₄)₂ wherein R₄ is H oralkyl of 1 to 6 carbon atoms which may be straight chain or branched;COOR₄ ; CH₂ OR₄ ; formyl; CN; trifluoromethylthio; or nitro; each R' isindependently R₄ ; OR₄ ; COOR₄ ; N(R₄)₂ ; SR₄ ; CH₂ OR₄ ; CHO; ortogether R' and R' are O; CH₂ ; or ##STR44## Y' is sulfur,sulfoxide,sulfone; ##STR45## R₁₁ is H, alkyl of 1-4 carbon atoms whichmay be straight chain or branched; alkanoyl of 1-4 carbon atoms whichmay be straight chain or branched; phenylsulfonyl; tosyl; NR₁₂ whereinR₁₂ is H, alkyl of 1-4 carbon atoms which may be straight chain orbranched; or ##STR46## wherein R₁₃ is alkyl of 1-4 carbon atoms whichmay be straight chain or branched, alkoxy of 1-4 carbon atoms which maybe straight chain or branched; N--CN, CH₂, or C═O; Y is Y' and oxygen;each R₁ is independently hydrogen or alkyl of 1-3 carbon atoms; each mis independently an integer from 0-6; R₂ is ##STR47## each R₆ isindependently H or alkyl of 1-4 carbons; each R₇ is independently H, OH,or alkyl of 1-4 carbons; each R₈ is independently H, or alkyl of 1-4carbons, and is absent when a triple bond is present; R₅ is COOR₄ ; CH₂OH; CHO; tetrazole; NHSO₂ R₁₄ ; hydroxymethylketone; CN; CON(R₇)₂ ; amonocyclic or bicyclic heterocyclic ring containing an acidic hydroxylgroup; or COOR₁₅ where R₁₅ is ##STR48## wherein each s is independently0-3; R₁₆ isA) a monocyclic or bicyclic heterocyclic radical containingfrom 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatomsselected from N and S with at least one being N, and with each ring inthe heterocyclic radical being formed of 5 or 6 atoms, or B) the radicalW--R₁₇ wherein W is O, S or NH and R₁₇ contains up to 21 carbon atomsand is (1) a hydrocarbon radical or (2) an acyl radical of an organicacyclic or monocyclic carboxylic acid containing not more than 1heteroatom in the ring; R14 is OH, alkyl or alkoxy of 1 to 6 carbonatoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms; r an q areeach independently 0-20 provided that the total of r and q does notexceed 20; p is 0 or 1; R₃ is alkyl of 1 to 6 carbon atoms which may bestraight chain or branched; or alkenyl of 3 to 6 carbon atoms which maybe straight chain or branched as illustrated in formulas IV and V; R₉ isalkyl of 1 to 6 carbon atoms which may be straight chain or branched;alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;or (CH₂)_(r) R₅ ; and R₁₀ is H; alkyl of 1 to 6 carbon atoms which maybe straight chain or branched; ##STR49## or R₄ OCH₂ --.
 15. A methodaccording to claim 14 wherein the compound has an IC₅₀ equal to or lessthan 10 μM in the hPPARδ binding assay and an EC₅₀ equal to or less than10 μM in the hPPARδ transactivation assay.
 16. The method of claim 15wherein the compound has an IC₅₀ equal to or less than 100 nM in thehPPARδ binding assay and an EC₅₀ equal to or less than 100 nM in thehPPARδ transactivation assay.
 17. The method of claim 16 wherein thecompound has an IC₅₀ equal to or less than 50 nM in the hPPARδ bindingassay and an EC₅₀ equal to or less than 50 nM in the hPPARδtransactivation assay.
 18. The method of claim 17 wherein the compoundhas an IC₅₀ equal to or less than 10 nM in the hPPARδ binding assay andan EC₅₀ equal to or less than 10 nM in the hPPARδ transactivation assay.19. A method for halting, preventing or reducing the risk of developingatherosclerosis and related disease events which comprises administeringto a patient in need thereof an effective amount of a compound of claim9 in combination with a sulfonylurea, fibrate, HMG-CoA reductaseinhibitor, beta-sitosterol inhibitor, cholesterol acyltransferaseinhibitor, biguanides, cholestyramine, angiotensin II antagonist,melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin,α-glucosidase inhibitors, insulin secretogogue or insulin.
 20. A methodaccording to claim 19 wherein the compound has an IC₅₀ equal to or lessthan 10 μM in the hPPARδ binding assay and an EC₅₀ equal to or less than10 μM in the hPPARδ transactivation assay.
 21. The method of claim 20wherein the compound has an IC₅₀ equal to or less than 100 nM in thehPPARδ binding assay and an EC₅₀ equal to or less than 100 nM in thehPPARδ transactivation assay.
 22. The method of claim 21 wherein thecompound has an IC₅₀ equal to or less than 50 nM in the hPPARδ bindingassay and an EC₅₀ equal to or less than 50 nM in the hPPARδtransactivation assay.
 23. The method of claim 22 wherein the compoundhas an IC₅₀ equal to or less than 10 nM in the hPPARδ binding assay andan EC₅₀ equal to or less than 10 nM in the hPPARδ transactivation assay.